Mild methylenetetrahydrofolate reductase deficiency accelerates liver triacylglycerol and uric acid accumulation in fructose-fed mice.

A genetic predisposition to hepatic steatosis may be associated with dietary patterns. We hypothesized that a common variant in human methylenetetrahydrofolate reductase (MTHFR 677C→T) was previously associated with an increased risk of nonalcoholic fatty liver disease (NAFLD). In this study, we investigated the relationship between the human MTHFR polymorphism and NAFLD using fructose-fed male C57BL/6 Mthfr+/+ and Mthfr+/- mice, a model for the human gene variant. Mice were fed an 8% fructose solution for 12 weeks. Mthfr+/- mice had significantly increased abdominal fat mass and hepatic triglyceride (TG) but displayed a similar liver mass when compared with Mthfr+/+ mice. Liver morphology showed that mild MTHFR deficiency induced liver lipid droplet deposition and inflammatory cell infiltration, suggesting accelerated lipid accumulation in the liver. Moreover, mild MTHFR deficiency increased hepatic xanthine oxidase activity and uric acid accumulation. Using untargeted lipidomics, we identified 116 differentially expressed lipids species in the liver of Mthfr+/- mice when compared with Mthfr+/+ animals. The most significant lipid increase was observed in 47 TGs, followed by 33 phosphatidylcholines in Mthfr+/- mice liver. When compared with Mthfr+/+ liver, 9 TGs were dramatically decreased in Mthfr+/- liver. These changes were associated with upregulated gene expressions related to triglyceride synthesis and storage. Thus, Mthfr+/- mice developed NAFLD disease. These findings suggested the Mthfr variant may be at an increased risk of liver steatosis on a fructose solution diet.